Biomedical subjects

Masashi Shiomi

Publications and source records attributed to Masashi Shiomi.

At least 19 recordsLinked to original sources

PubMed2007

99mTc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits.

PURPOSE: Apoptosis is commonly observed in advanced atherosclerotic lesions. 99mTc-annexin A5 (99mTc-annexin V) has been proposed as a potential tracer for imaging apoptosis in atherosclerotic plaques. Accordingly, we determined the usefulness of 99mTc-annexin A5 as an atherosclerosis imaging tracer in a rabbit model (myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits; WHHLMI rabbits) of spontaneous atherosclerosis. METHODS: The WHHLMI and control rabbits were injected intravenously with 99mTc-annexin A5. After in vivo planar imaging, the radioactivity in the aorta was measured. Autoradiography, TUNEL staining, Azan-Mallory staining and immunohistological studies were performed serially throughout the aorta. RESULTS: 99mTc-Annexin A5 accumulation in the aorta of the WHHLMI rabbits was 5.6-fold higher than in that of control rabbits. Autoradiography showed heterogeneous multifocal accumulation of 99mTc-annexin A5 in WHHLMI rabbits. 99mTc-Annexin A5 accumulation was highest in the atheromatous lesions (6.2+/-2.5, %IDxBW/mm2x10(3)), followed in decreasing order by neointimal (4.9+/-1.3), fibroatheromatous (4.5+/-1.9), and collagen-rich lesions (3.3+/-1.4). The regional 99mTc-annexin A5 accumulation was significantly correlated with the TUNEL-positive cell density, macrophage density and "vulnerability index," an index of the morphological destabilized characteristics. The in vivo imaging clearly visualized the atherosclerotic lesions in WHHLMI rabbits. CONCLUSION: The present study in WHHLMI rabbits showed higher 99mTc-annexin A5 accumulation in grade IV atheroma than in other more stable lesions. 99mTc-Annexin A5 may be useful in identifying atheroma that is at higher risk for rupture and possibly in assessing the response to anti-atherosclerotic therapy.

Animals↗

PubMed2006

Lp(a) enhances coronary atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits.

Elevated plasma levels of LDL and lipoprotein (a) [Lp(a)] are associated with an increased risk of atherosclerosis and coronary heart disease. However, it is not known whether Lp(a) would enhance the atherogenic effect of LDL on coronary atherosclerosis and myocardial infarction. To address this issue, we cross-bred human Lp(a) transgenic (Tg) rabbits with Watanabe heritable hyperlipidemic (WHHL) rabbits and evaluated the long-term (at the age of 2 years) effects of Lp(a) on the development of coronary atherosclerosis. Compared to non-Tg WHHL rabbits, Tg WHHL rabbits did not show significant changes in plasma total cholesterol, triglycerides, or HDL-C. However, Tg WHHL rabbits showed significantly larger lesions in the right coronary arteries (p<0.05). Immunohistochemical staining revealed that the lesions of Tg WHHL rabbits were enriched in the extracellular matrix contents whereas the cellular components were not different from those in non-Tg WHHL rabbits. Increased atherosclerosis in the coronary arteries in Tg WHHL rabbit hearts was also associated with a higher incidence of chronic ischemia and myocardial infarction. These results suggest that increased plasma levels of Lp(a) enhance coronary atherosclerosis and myocardial infarction in the setting of hypercholesterolemia.

Animals↗

PubMed2006

G-CSF prevents the progression of atherosclerosis and neointimal formation in rabbits.

Granulocyte colony-stimulating factor (G-CSF) prevents left ventricular remodeling after myocardial infarction, but its effect on atherosclerosis is unknown. We examined two kinds of rabbit atherosclerosis models. Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHL-MI) rabbits were treated with G-CSF or saline for 7 days from 14 months old. The vascular injury models were created by inflating angioplasty balloon in the iliac artery of rabbits and were divided into G-CSF and saline group. G-CSF significantly reduced the stenosis score of coronary artery and lipid plaque area of thoracic aorta in WHHL-MI rabbits at 4 weeks after the treatment. In the vascular injury model, G-CSF significantly prevented an increase in neointima/media ratio at 4 weeks after the treatment. G-CSF accelerated the reendothelialization of denuded arteries, and the pretreatment with nitric oxide synthase inhibitor significantly inhibited it. These results suggest that G-CSF has a therapeutic potential for the progression of atherosclerosis.

Animals↗

PubMed2006

Seasonal distribution and phylogenetic analysis of human metapneumovirus among children in Osaka City, Japan.

BACKGROUND: Human metapneumovirus (hMPV) is one of the etiological agents of respiratory tract infection (RTI). Because clinical symptoms of hMPV resemble those caused by respiratory syncytial virus (RSV), clinical diagnosis of hMPV infection is difficult. Moreover, hMPV isolation using cultured cells is generally difficult and not efficient compared with reverse transcription-PCR (RT-PCR). OBJECTIVES: To assess infection and seasonal distribution of hMPV associated with RTI among children in Osaka City, Japan. STUDY DESIGN: To detect the hMPV gene, we extracted viral RNA from clinical specimens of patients with RTI and performed RT-PCR or nested-PCR for the fusion (F) gene. hMPV-specific amplicons were sequenced and subjected to phylogenetic analysis. RESULTS: From June 2004 to May 2005, we detected 29 (20.1%) hMPV strains among 144 clinical specimens. Fifteen strains were detected by RT-PCR and the remaining 14 by nested-PCR. Prevalence was principally in winter and spring with incidence peaking in April. We also detected the hMPV RNA from a patient with encephalitis. Approximately 80% of the hMPV-positive patients were younger than 3 years. To analyze these isolates precisely, a phylogenetic analysis using F gene was performed and demonstrated that Osaka City isolates of hMPV consists of two major genetic lineages each comprising two sublineages. CONCLUSIONS: We found two major genetic lineages of hMPV in Osaka City, Japan. We also found that nested-PCR was an efficient method for detecting the hMPV gene in clinical specimens. Of the 28 patients presenting with hMPV infection, 1 patient had associated encephalitis suggesting that hMPV infection might play a role in inducing encephalitis.

Adolescent↗

PubMed2006

Pathogenesis of tendinous xanthoma: histopathological study of the extremities of Watanabe heritable hyperlipidemic rabbits.

BACKGROUND: Tendinous xanthomas associated with heritable hyperlipidemia are clinically well known. Nevertheless, there have been few basic investigations of the pathogenesis of these xanthomas. To clarify the pathogenesis of these xanthomas, we examined the localization and histopathological features of xanthomatous tissues in the extremities of Watanabe heritable hyperlipidemic (WHHL) rabbits. METHODS: Twenty-six WHHL rabbits at 1-31 months of age were dissected to observe the localization of xanthomas. In the histopathological study, tendons and ligaments that included xanthomatous tissues were sectioned and stained with hematoxylin and eosin, Masson's trichrome, and toluidine blue. Immunohistochemical staining was performed with RAM-11, a monoclonal antibody specific for rabbit macrophages, and CD31, a monoclonal antibody specific for endothelial cells. RESULTS: At necropsy examination, spontaneous development of xanthomas was observed in the plantar side of the plantaris tendon, the flexor retinaculum of the carpus, and around the digital flexor tendons of each joint level. Xanthoma formation was observed from 10 months of age and progressed with advancing age. The histomorphological study revealed that xanthomas had developed in superficial paratenon of the tendons that wrap around bony or fibrous pulleys. Many fibrocartilage cells were observed in the deep side of affected tendons. A large number of blood vessels were seen in the xanthomatous tissues of these WHHL rabbits. Immunohistochemical evaluation revealed that the xanthoma plaques contained endothelial cells and macrophages. CONCLUSIONS: It is likely that mechanical stress and extensive vascularization are essential factors for xanthoma formation. Moreover, endothelial cells and macrophages cells are principal contributors to the pathogenesis of tendinous xanthomas and to atherogenesis.

Animals↗

PubMed2006

[Neuroradiological findings in the acute stage of influenza encephalopathy].

Influenza encephalopathy(IE) is characterized by its high incidence in Japanese children between 1 year and 5 years of age, its onset in the first or the second day of illness and its high mortality (15-30%) and morbidity (25-40%). We proposed the classification of IE with poor prognosis from the neuroradiological findings. Four types of encephalopathy seem to be differentiated from each other, 1. acute necrotising encephalopathy(ANE) type, 2. hemorrhagic shock and encephalopathy syndrome (HSES) type, 3. acute brain swelling(ABS) type, 4. acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) type. The notable radiological features are thalamic lesions in ANE, diffuse cerebral cortical cytotoxic edema in HSES, reversible cerebral swelling in ABS which sometimes reaches lethal brain herniation, and localised cerebral edema which is called as "lobar edema" because its extent seems to be equivalent to cerebral lobes. "Lobar edema" is developed about four days after status epilepticus simultaneously with the onset of repetitious focal seizure and neurological deterioration. The radiological changes in the early phase of IE are described in each types. In conclusion IE is a constellation of different types of encephalopathy although a further research of encephalopathy is urgently needed.

Acute Disease↗

PubMed2006

Application of 18F-FDG PET for monitoring the therapeutic effect of antiinflammatory drugs on stabilization of vulnerable atherosclerotic plaques.

UNLABELLED: The rupture of atherosclerotic vulnerable plaques and subsequent formation of thrombi are the main factors responsible for myocardial and cerebral infarctions. Because macrophage infiltration plays an essential role in plaque rupturing, pharmacologic therapy that reduces macrophage infiltration is required to stabilize the vulnerable plaques. The monitoring of therapeutic effect is important in assessing the therapeutic effects of drugs for individual patients. We previously reported that (18)F-FDG accumulates in macrophage-rich plaques. The present study was undertaken to investigate the usefulness of (18)F-FDG PET for monitoring therapies that target vascular inflammation. METHODS: Myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits were used in this study. The antioxidant probucol was included in the diet fed to 4 rabbits starting at 10 mo of age (probucol group). In a control study, 4 rabbits received standard rabbit chow (control group). (18)F-FDG PET experiments were performed on both groups before the study and at 1, 3, and 6 mo after treatment. After the last imaging session, the rabbits were sacrificed at 3 h after injection of (18)F-FDG, and the aortas were removed. The accumulated radioactivity was then measured, and the number of macrophages was determined by examination of stained sections. RESULTS: At the age of 10 mo, before the treatment, the aorta could be imaged by (18)F-FDG PET in all rabbits. The aorta could not be imaged after 6 mo of probucol treatment, whereas intense radioactivity was observed in the control rabbits throughout the investigation. The standardized uptake values (SUVs) of the aorta were decreased significantly in the probucol group after 3 mo of intervention as compared with the pretreatment period. The SUVs of the control group were increased gradually at 6 mo. Radioactivity in the aorta was significantly lower in the probucol group than that in the control group. Macrophages were already present at the beginning of the study, and probucol treatment for 6 mo resulted in a significant reduction of macrophage infiltration. CONCLUSION: (18)F-FDG PET was able to image the reduction of inflammation by probucol. (18)F-FDG PET should be useful for evaluating the therapeutic effect of drugs clinically and for the development of new drugs that can stabilize vulnerable plaques. (18)F-FDG PET should be useful for evaluating the therapeutic effect of drugs clinically and for the development of new drugs that can reduce inflammation of vulnerable plaques.

Animals↗

PubMed2005

Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase.

OBJECTIVE: This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency. METHODS: We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits. RESULTS: Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006-1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04-1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits. CONCLUSIONS: We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.

Animals↗

PubMed2005

Atheroma stabilizing effects of simvastatin due to depression of macrophages or lipid accumulation in the atheromatous plaques of coronary plaque-prone WHHL rabbits.

Clinical studies showed that both hydrophilic and lipophilic statins reduce coronary events although in vitro studies demonstrated that lipophilic statins inhibited proliferation of arterial smooth muscle cells. Therefore, we examined whether lipophilic simvastatin reduces smooth muscle cells in atheromatous plaque and how simvastatin affects stability of atheroma in vivo. Coronary atherosclerosis-prone WHHLCA rabbits aged 10 months were given simvastatin (15 mg/kg) orally for 52 weeks and examined the serum lipid levels, plasma drug concentration, and aortic and coronary atherosclerosis. Compared to the placebo group, the plasma cholesterol levels decreased by about 20%. In the simvastatin group, the lipid component (macrophages+extracellular lipids) was decreased in the coronary and aortic atheroma, despite no decrease in the fibromuscular components. Consequently, the frequency of vulnerable plaque decreased. In the coronary plaque of the simvastatin group, PCNA-positive cells (which appeared to be macrophages) of the plaques decreased but the TUNEL-positive cells did not show significant change. Finally, fully differentiated smooth muscle cells increased in the aortic lesions of the simvastatin group. In conclusion, our results suggest that simvastatin did not depress the fibromuscular components in atheromatous plaques and the plaque-stabilizing effects were due to the reduction of macrophages/lipid deposits.

Animals↗

PubMed2005

C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance.

C-reactive protein (CRP) is frequently deposited in the lesions of the arterial intima; however, the origin and pathological significance of CRP in these lesions are not completely understood. In this study, we measured CRP levels in the plasma of hypercholesterolemic rabbits and investigated CRP expression at both the mRNA and protein levels using rabbit and human atherosclerotic specimens. CRP levels were significantly elevated in both cholesterol-fed and Watanabe heritable hyperlipidemic rabbits, and CRP levels were clearly correlated with aortic atherosclerotic lesion size. Immunohistochemical staining coupled with Western blotting analysis revealed that CRP-immunoreactive proteins were found at all stages of atherosclerosis from the early to advanced lesions. CRP was present extracellularly and co-localized with apolipoprotein B but was rarely associated with the cytoplasm of macrophages and foam cells. Real-time reverse transcriptase-polymerase chain reaction analysis revealed that CRP mRNA in atherosclerotic lesions was barely detectable, and isolated macrophages did not express CRP mRNA, suggesting that CRP proteins found in the lesions were essentially derived from the circulation rather than synthesized de novo by vascular cells. These results suggest that there is a link between plasma CRP and the degree of atherosclerosis and that inhibition of plasma CRP may represent a therapeutic modality for the treatment of cardiovascular disease.

Animals↗

PubMed2005

Discrimination of recent ischemic myocardial changes in WHHLMI rabbits from the findings of postmortem degeneration.

To distinguish recent ischemic myocardial changes in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits from general postmortem myocardial degeneration, we examined hearts of WHHLMI rabbits after sudden death and postmortem hearts of non-atherogenic rabbits. Hearts of 8 WHHLMI rabbits were excised within 30 min of sudden death and hearts of 27 non-atherosclerotic rabbits were excised at designated periods after sacrifice. A large number of myocardial cells from WHHLMI rabbits exhibited features characteristic of ischemia (intercellular gap, intracellular edema, eosinophilia, disappearance of myocardial cells, indistinct nuclei, wavy myocardial fibers) simultaneously at regions close to proximal occluded coronary arteries. Although postmortem hearts of non-atherosclerotic rabbits exhibited similar characteristics, several features characteristic of autolyzed myocytes were also randomly observed in the left ventricle wall. Each feature was detected independently in myocardial cells or regions of the ventricle wall. In conclusion, we found several unique characteristics associated with myocardial infarction which enable discrimination between recent ischemic myocardial changes and myocardial degeneration following death.

Animals↗

PubMed2004

Novel insights into coronary lumen preservation during progression of coronary atherosclerosis in coronary atherosclerosis-prone rabbits.

BACKGROUND: In coronary atherosclerosis-prone Watanabe heritable hyperlipidaemic (WHHLCA) rabbits, an animal model for low-density lipoprotein receptor deficiency and spontaneous coronary atherosclerosis, the coronary arteries show compensatory remodelling during the progression of atherosclerosis. Therefore, we analysed coronary remodelling of WHHLCA rabbits quantitatively using a method that eliminates the limitations of previous analytical methods. METHODS: Arterial remodelling was evaluated in perfusion-fixed coronary arteries of 11 WHHLCA rabbits using both new and previous analyses. With the improved methods removing limitations on quantitative analysis of arterial remodelling, we evaluated how lumen area or arterial size changed with accumulating atherosclerotic plaques compared to before plaque development. The original lumen area before plaque development was calculated using the diameter-length relationship. Wall shear stress change ratio was calculated from changes in arterial size. RESULTS: Using the old analytical method (and as seen in similar human studies), lumen area increased up to a level of 29% of cross-sectional narrowing. However, with the improved analysis, in cross-sectioning narrowing at levels below 10%, the lumen area modestly decreased, and when the cross-sectional narrowing ranged from 10-68%, the lumen area remained constant, and diminished sharply despite continued remodelling when cross-sectional narrowing reached 70% or above. Arterial remodelling progressed quantitatively to a slight increase in arterial wall shear stress as well as lumen area up to a level of 70% cross-sectional narrowing. CONCLUSIONS: These findings demonstrate marked influences of arterial tapering and individual variation of arterial size on quantitative analysis of arterial remodelling, and provide the novel insight that coronary compensatory remodelling in atherosclerosis maintains the lumen size up to levels of 70% cross-sectional narrowing in proportion to wall shear stress.

Animals↗

PubMed2004

Age-related changes in serum/plasma biochemical parameters of WHHLMI rabbits.

We developed myocardial infarction-prone rabbits (WHHLMI rabbits) by selectively breeding coronary atherosclerosis-prone WHHL rabbits. To examine the serum/plasma biochemical parameters of this animal model, we assayed the lipid and glucose levels, and enzyme activities of WHHLMI rabbits from 2 to 26 months of age using solid phase analysis. The results showed a good correlation with those measured with a conventional method. The serum enzyme activities and lipid levels varied with aging despite almost no change in the plasma glucose levels. Gender differences were observed in the total cholesterol, triglyceride, and lactate dehydrogenase activity levels. The data on these serum/plasma biochemical parameters will be useful in studies of myocardial infarction or pharmacological studies using this model.

Age Factors↗

PubMed2004

Progression of coronary atherosclerosis relates to the onset of myocardial infarction in an animal model of spontaneous myocardial infarction (WHHLMI rabbits).

Recently, we developed myocardial infarction-prone WHHLMI rabbits from coronary atherosclerosis-prone WHHL rabbits (WHHLCA rabbits) by selective breeding. In this study, we examined the relation of atherosclerotic plaques to the onset of myocardial infarction. We examined myocardial lesions of 378 WHHL rabbits born between 1992 and 2000, and atherosclerosis lesions of 93 WHHLCA and 82 WHHLMI rabbits. The aortic lesions were evaluated as percent surface lesion area. The coronary lesions were evaluated as cross sectional narrowing using sections prepared at 500 or 1,000 microm intervals. Serum lipid levels were assayed with enzymatic methods. The cumulative incidence of fatal myocardial infarction between 11 and 35 months old was 90% in WHHLMI rabbits and 21% in WHHLCA rabbits, respectively. Selective breeding increased the serum cholesterol levels by about 200 mg/dl despite there being no changes in triglyceride levels. Aortic and coronary atherosclerosis progressed markedly in WHHLMI rabbits compared to WHHLCA rabbits. Especially, WHHLMI rabbits over 15 months old showed more than 90% cross sectional narrowing of the left circumflex arteries, main stem of the left coronary artery, and the origin portion of the right coronary artery. In addition, there were no gender differences in atherosclerotic lesions of both aortas and coronary arteries. In conclusion, the present study showed that marked progression of coronary atherosclerosis was probably associated with spontaneous development of myocardial infarction in WHHLMI rabbits.

Animals↗

PubMed2004

Correlation of vulnerable coronary plaques to sudden cardiac events. Lessons from a myocardial infarction-prone animal model (the WHHLMI rabbit).

It is generally considered that coronary rupture-prone plaques play an important role in the onset of sudden cardiac events (acute coronary syndromes/sudden cardiac death). However, it is not clear which factors or stimuli are required to trigger plaque rupture and whether coronary plaques without occlusive thrombi can cause sudden cardiac events. To address these issues, recently, we developed a rabbit model of spontaneous myocardial infarction [the Watanabe heritable hyperlipidemic (WHHL) MI rabbit] and found that this model possessed several types of coronary plaques that are possibly correlated to sudden cardiac events. Although many of the coronary plaques of the WHHLMI rabbits appeared histologically to be rupture-prone in nature, true rupture was detected only in the few animals that died of MI. In addition, no occlusive thrombus was detected in any WHHLMI rabbit. These findings suggest that some additional stimuli play a definitive role in causing disruption of rupture-prone plaques and thrombosis. Nearly-occluded plaques caused by a luminal macrophage accumulation are the most common feature of WHHLMI rabbits, suggesting that they are responsible for sudden cardiac events. The WHHLMI rabbit could be a useful model for studying the mechanism(s) of plaque rupture and thrombogenesis if plaque rupture/thrombus formation is induced in the rupture-prone plaques of WHHLMI rabbits by administration of additional triggering factors, and could provide a novel means for developing new therapies.

Animals↗

PubMed2004

(18)F-FDG accumulation in atherosclerotic plaques: immunohistochemical and PET imaging study.

UNLABELLED: The rupture of atherosclerotic plaques and the subsequent formation of thrombi are the main factors responsible for myocardial and cerebral infarctions. Thus, the detection of vulnerable plaques in atherosclerotic lesions is a desirable goal, and attempts to image these plaques with (18)F-FDG have been made. In the present study, the relationship between the accumulation of (18)F-FDG and the biologic characteristics of atherosclerotic lesions was investigated. Furthermore, PET imaging of vulnerable plaques was performed with an animal model of atherosclerosis, Watanabe heritable hyperlipidemic (WHHL) rabbits. METHODS: WHHL (n = 11) and control (n = 3) rabbits were injected intravenously with (18)F-FDG, and the thoracic and abdominal aortas were removed 4 h after injection. The accumulated radioactivity was measured, and the number of macrophages and the intimal area were investigated by examination of stained sections. PET and CT images were also acquired at 210 min after injection of the radiotracer. RESULTS: (18)F-FDG accumulated to a significantly higher level in the aortas of the WHHL rabbits (mean +/- SD differential uptake ratio [DUR], 1.47 +/- 0.90) than in those of the control rabbits (DUR, 0.44 +/- 0.15); DUR was calculated as (tissue activity/tissue weight)/(injected radiotracer activity/animal body weight), with activities given in becquerels and weights given in kilograms. (18)F-FDG uptake and the number of macrophages were strongly correlated in the atherosclerotic lesions of the WHHL rabbits (R = 0.81). In the PET analysis, intense (18)F-FDG radioactivity was detected in the aortas of the WHHL rabbits, whereas little radioactivity was seen in the control rabbits. CONCLUSION: The results suggest that macrophages are responsible for the accumulation of (18)F-FDG in atherosclerotic lesions. Because vulnerable plaques are rich in macrophages, (18)F-FDG imaging should be useful for the selective detection of such plaques.

Animals↗

PubMed2003

Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity.

Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of the triglyceride-rich lipoproteins and plays a critical role in lipoprotein and free fatty acid metabolism. Genetic manipulation of LPL may be beneficial in the treatment of hypertriglyceridemias, but it is unknown whether increased LPL activity may be effective in lowering plasma cholesterol and improving insulin resistance in familial hypercholesterolemic patients. To test the hypothesis that stimulation of LPL expression may be used as an adjunctive therapy for treatment of homozygous familial hypercholesterolemia, we have generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits that overexpress the human LPL transgene and compared their plasma lipid levels, glucose metabolism, and body fat accumulation with those of non-Tg WHHL rabbits. Overexpression of LPL dramatically ameliorated hypertriglyceridemia in Tg WHHL rabbits. Furthermore, increased LPL activity in male Tg WHHL rabbits also corrected hypercholesterolemia (544 +/- 52 in non-Tg versus 227 +/- 29 mg/dl in Tg, p < 0.01) and reduced body fat accumulation by 61% (323 +/- 27 in non-Tg versus 125 +/- 21ginTg, p < 0.01), suggesting that LPL plays an important role in mediating plasma cholesterol homeostasis and adipose accumulation. In addition, overexpression of LPL significantly suppressed high fat diet-induced obesity and insulin resistance in Tg WHHL rabbits. These results imply that systemic elevation of LPL expression may be potentially useful for the treatment of hyperlipidemias, obesity, and insulin resistance.

Adipose Tissue↗

PubMed2003

Development of an animal model for spontaneous myocardial infarction (WHHLMI rabbit).

OBJECTIVE: Coronary heart disease is the most common cause of death in developed countries. However, there are no suitable animal models that mimic spontaneous myocardial infarction in humans. In this study, we attempted to obtain a rabbit strain with spontaneous myocardial infarction by selective breeding of coronary atherosclerosis-prone Watanabe heritable hyperlipidemic (WHHL) rabbits, designated as WHHLMI rabbits. METHODS AND RESULTS: WHHLMI rabbits were characterized by the high incidence of fatal myocardial infarction at ages 11 to 35 months, being increased from 23% to 97% after the selective breeding. The ECG on WHHLMI rabbits showed a typical feature of myocardial infarction. Histological examination of hearts from suddenly deceased WHHLMI rabbits revealed old myocardial infarction accompanied by fresh myocardial lesions. The culprit coronary arteries exhibited severe atheromatous plaques (>90% lumen area stenosis), suggesting that coronary atherosclerosis is responsible for myocardial infarction observed in WHHLMI rabbits. In addition, the coronary plaques showed vulnerable features including macrophage-rich thin cap and large necrotic core. CONCLUSIONS: To the best of our knowledge, this is the first report of spontaneous myocardial infarction in rabbits, and it is suggested that this WHHLMI rabbit strain will be a useful animal model to study human myocardial infarction.

Animals↗